STOPPING RULES IN FIRST ENTRY INTO HUMAN STUDIES

Transcription

1 STOPPING RULES IN FIRST ENTRY INTO HUMAN STUDIES Club Phase 1 Working Party: Alain Patat, Yves Donazzolo, Henri Caplain, Stephan Chalon, Michel Sibille Joint Conference of European Human Pharmacological Societies and 20th Anniversary of AGAH AGAH, CLUB PHASE I, AHPPI & BAPU BERLIN, 31 Mar - 01 APR

2 WHY French Club Phase I Working group : Br J Clin Pharmacol : French Club Phase I Working group: A safety grading scale to support dose escalation and define stopping rules for healthy subjects first-entry-into-man studies. Br J Clin Pharmacol : New requests by regulatory authorities after TGN 1412 tragedy London 2006 Improve and facilitate decision making in dose escalation studies as requested by EMA guideline on Strategy to Identify Mitigate Risks for First in Human Clinical trials with Investigational Medicinal Products Using risk assessment & minimization strategy 2

3 HOW & SCOPE Needs: Standardisation of methods for an accurate and relevant grading of adverse events & clinical findings Clinically relevant & accepted «Stopping rules» Individual level Group/cohort level Applicable to FIH studies conducted in young male subjects First-in-Human dose escalation studies (single & multiple dose) Healthy subjects AP 3 3

4 CURRENT AVAILABLE GUIDELINES Nothing relevant and accepted subject participating in FIHs fitting well to healthy 1. WHO Recommendations for grading Acute & subacute toxic effects WHO Handbook for reporting results of cancer treatment (1981) 2. NCI Common Terminology Criteria for Adverse Events (CTCAE v4 Sept 2009) Only applicable to oncology 3. NIH Division of AIDS (Dec 2004) : Table for grading the severity of adult and paediatric adverse events 4. FDA Guidance for Industry (Sept 2007) : Toxicity grading scale for adult and adolescent volunteers enrolled in preventive vaccine clinical trials. controversy in-between organizations (2005) not relevant enough to healthy subjects 4

5 NEED OF RELEVANT PROPOSALS CPI proposals.../... 5

6 PREAMBULE : DEFINITION & WORDING ADVERSE EVENT OR FINDING Adverse Event (ICH definition): «any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship to this treatment». Any spontaneously reported or observed AE to be collected 6

7 PREAMBULE : DEFINITION & WORDING ADVERSE EVENT OR FINDING Clinical event = ADVERSE EVENT Non-clinical (vital signs, ECG, routine laboratory tests ) event = FINDING 7

8 IS THE EVENT RELATED? Investigator judgement: «unrelated, unlikely, possible, probable, (likely) or definite» Final judgement / coding : binary process (related or not related ) Low imputability power due to small number of subjects Clear proof of intercurrent disease: non-related If not => related 8

9 QUOTATION? USE OF THE NIH / FDA GRADING Grading: use NIH/FDA 4-level scales of intensity: 1. Grade 1 : mild : Does not interfere with daily activity 2. Grade 2 : moderate : Interferes with daily activity; no treatment excepted acetaminophen (limited amount) 3. Grade 3 : severe : Prevents daily activity or requires treatment (or medical intervention - FDA) 4. Grade 4 : life-threatening : Emergency room visit or disabling or hospitalization 9

10 FIRSTLY Application to clinical AEs à quotation directly derived from observed severity/intensity or from daily life consequences 10

11 Intensity Grade 1 Grade 2 Grade 3 General definition Does not interfere with activity Modulation and upgrading based on: Headache FDA headache NIH headache APPLICATION TO CLINICAL AEs number of episodes and/or Transient No interference with activity HEADACHE Symptoms causing no or minimal interferences with usual social & functional activities 11

12 Intensity Grade 1 Grade 2 Grade 3 General definition Modulation and upgrading based on: Does not interfere with activity number of episodes and/or Interferes with activity, no treatment except acetaminophen duration of symptoms and/or Headache Transient Interferes with activity e.g. several hours but less <12 hours. no treatment except acetaminophen FDA headache NIH headache APPLICATION TO CLINICAL AEs No interference with activity Symptoms causing no or minimal interferences with usual social & functional activities HEADACHE Repeated use of non-narcotic pain reliever > 24 hours or some interference with activity Symptoms causing greater than minimal interferences with usual social & functional activities 12

13 Intensity Grade 1 Grade 2 Grade 3 General definition Modulation and upgrading based on: Does not interfere with activity number of episodes and/or Interferes with activity, no treatment except acetaminophen duration of symptoms and/or Headache Transient Interferes with activity e.g. several hours but less <12 hours. no treatment except acetaminophen FDA headache NIH headache APPLICATION TO CLINICAL AEs No interference with activity Symptoms causing no or minimal interferences with usual social & functional activities HEADACHE Repeated use of non-narcotic pain reliever > 24 hours or some interference with activity Symptoms causing greater than minimal interferences with usual social & functional activities Prevents daily activity or requires treatment significant associated malaise or general effects Prevents daily activity e.g. > 12 h, presence during the night. or requires treatment Significant; any use of narcotic pain reliever or prevents daily activity Symptoms causing inability to perform usual social & functional activities 13

14 APPLICATION TO CLINICAL AEs VOMITING Intensity Grade 1 Grade 2 Grade 3 Vomiting 1 episode FDA Nausea/vomiting NIH vomiting No interference with activity or 1-2 episodes Transient or intermittent vomiting with no or minimal interference with normal intake 14

15 APPLICATION TO CLINICAL AEs VOMITING Intensity Grade 1 Grade 2 Grade 3 Vomiting 1 episode 2 to 4 episodes/day or 2/day x 2 days FDA Nausea/vomiting NIH vomiting No interference with activity or 1-2 episodes Transient or intermittent vomiting with no or minimal interference with normal intake Some interference with activities or >2 episodes/24 hours Frequent episodes of vomiting with no or mild dehydration 15

16 Intensity Grade 1 Grade 2 Grade 3 Vomiting 1 episode 2 to 4 episodes/day or 2/day x 2 days FDA Nausea/vomiting NIH vomiting APPLICATION TO CLINICAL AEs No interference with activity or 1-2 episodes Transient or intermittent vomiting with no or minimal interference with normal intake VOMITING Some interference with activities or >2 episodes/24 hours Frequent episodes of vomiting with no or mild dehydration 4 episodes per day or 2 or more per day prolonged on several days Prevents daily activity or requires outpatient IV hydration Persistent vomiting resulting in orthostatic hypotension or aggressive rehydration indicated (e.g. IV fluids) 16

17 SECONDLY Application to non-clinical findings Grade 1 17

18 APPLICATION TO NON CLINICAL FINDINGS GRADE 1 Findings : vital signs, ECG & lab tests Grading based on the likelihood of risk or consequence Use of a relevant method to determine the threshold between spontaneous variation and potentially clinically significant abnormality. Existing & recognized threshold or rules: Disease definition (diabete, HTA, anemia) Published rule: Hy s law Combined method based on a threshold value (out of normal range) associated to a change from baseline exceeding spontaneous variability (out of changes range). 18

19 EXAMPLE ALT TRANSAMINASE Healthy young male subject database Sibille M, Deigat N, Durieu I, Guillaumont M,Morel D,Bienvenu J,Massignon D, Vital Durand D. Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials. Eur J Clin Pharmacol 1999; 55: Reference values: IU/L and Reference changes: + 10 IU/L Calculated threshold: 1.2 x Upper limit of NR (ULNR) 19

20 EXAMPLE ALT TRANSAMINASE Healthy young male subject database (Sibille et al. 1999) : Reference values: IU/L and Reference changes: + 10 IU/L Calculated threshold: 1.2 ULNR Application to Worldwide Accepted Normal Range (Case Records of the Massachusetts General Hospital: Laboratory Reference values : Alexander Kratz, Maryjane Ferraro, Patrick M. Sluss, and Kent B. Lewandrowski, NEJM 2004; 351: ) 0 35 IU/L (or μkat/l) Grade 1 proposals: 1.2 ULNR or 42 IU/L (35x1.2) 20

21 Healthy young male subject database (Sibille et al. 1999) : Reference values: µmol/l and Reference changes: + 15 µmol/l Calculated threshold: 1.1 ULNR EXAMPLE CREATININE Application to NEJM worldwide Normal Range (2004) : µmol/l Grade 1 proposals: 1.1 ULNR or 146 µmol/l (133x1.1). BUT 146 µmol/l is too high in young healthy subject : 125/130 sounds more relevant. 21

22 Determination of the Grade I threshold using Combined Method: Healthy subject database* (unpublished data, see also 9) Some examples 22

23 GRADE 1 THRESHOLD(S) : LAB PARAMETER French Club Phase I Working group : Br J Clin Pharmacol : Parameters LAB Unit Reference Values (Lower/ Upper limit of Normal ranges) Reference changes Decrease: (-) Increase (+) Median values Relative values to NR Lower Higher ALT IU/L *ULNR AST IU/L *ULNR Bilirubin µmol/l *ULNR Creatinine µmol/l *ULNR CPK IU/L * ULNR Neutrophils giga/l (-0.7*LLNR) *ULNR Platelets giga/l (- 0.85*LLNR) * applicable for young male subject 23

24 * These data are applicable for young male subject. On some parameters, an adaptation is required for females or elderly or black people. ** The reference values (normal ranges) shoud not necessarely be used as inclusion criteria. *** Due to frequency of Gilbert disease in young men the inclusion limit is

25 CONDITIONS & ADAPTATION Accurate sampling and assay conditions Use the Normal Range of the local laboratory of the Clinical Pharmacology Unit or of the NEJM (2004). Any finding requires a control before validation Consider relative - % of Upper or Lower LNR -, or absolute value, as appropriate Adjust to the studied population (women, elderly ) 25

26 ADJUST THE THRESHOLD ACCORDING TO THE USE OF BIOMARKERS SAFETY OR PHARMACODYNAMIC ACTIVITIES If potential PD effect: ie decreasing the glucose level with an antidiabetics will not be considered as a worrying AE but as a beneficial effect and the accepted lower limit of the glycemia will be very different increasing aptt with an anticoagulant drug is a beneficial effect and therefore threshold may be greater (3 ULNR used as stopping rule) 26

27 SECONDLY Application to non-clinical findings Grade 2 & 3 MSMS 27

28 APPLICATION TO NON CLINICAL FINDINGS GRADE 2 & 3 Nothing is recognized to define such thresholds!!! Except for some rare cases for ex Hy s law Proposal: Consensus approach CPI seniors : investigators & sponsors - consensus Consider CTCAE, WHO, FDA and NIH grades Submitted for internal agreement or comments to CPI members CPI suggest possible upgrading modulation * (Grade 2+): Rapid worsening Association to clinical signs Association to other abnormality ( ie Hy s law) Occurrence of safety signal in others subjects from the same cohort * FDA Draft guidance Oct

29 ALT PARAMETER Parameter Origin Grades CPI 1.2 to 3 ULNR 3 to 5 5 to 10 ALT (ULNR) AP 29

30 ALT PARAMETER Parameter Origin Grades CPI 1.3 to 3 ULNR 3 to 5 5 to 10 ALT (ULNR) FDA 1.1 to 2.5 ULNR 2.6 to 5 5 to 10 NIH 1.25 to 2.5 ULNR 2.5 to 5 5 to 10 AP The values are similar in the 3 proposals 30

31 BILIRUBIN PARAMETER Grades Parameter Origin Bilirubin (ULNR) CPI 1.3 to 2 ULNR if change from baseline > 10 mmol/l 2 to to 3 31

32 BILIRUBIN PARAMETER Grades Parameter Origin CPI 1.3 to 2 ULNR if change from baseline > 10 mmol/l 2 to to 3 Bilirubin (ULNR) FDA, if LFT normal 1.1 to 1.5 ULNR 1.6 to 2 2 to 3 32

33 BILIRUBIN PARAMETER Grades Parameter Origin CPI 1.3 to 2 ULNR if change from baseline > 10 mmol/l 2 to to 3 Bilirubin (ULNR) FDA, if LFT normal 1.1 to 1.5 ULNR 1.6 to 2 2 to 3 FDA, if increase of LFT *** 1.1 to to to 1.75 *** Draft FDA guidance. Drug-induced liver injury (2007) 33

34 BILIRUBIN PARAMETER Grades Parameter Origin Bilirubin (ULNR) CPI FDA, if LFT normal FDA, if increase of LFT *** 1.3 (or # 35 IU/L) to 2 ULNR if change from baseline > 10mmol/L 2 to to to 1.5 ULNR 1.6 to 2 2 to to to to 1.75 NIH 1.25 to 2.5 ULNR 2.5 to 5 5 to 10 NIH grade 2/3 limit seems too high and at risk 34

35 ROUTINE LABORATORY FINDINGS : LIVER GRADING French Club Phase I Working group : Br J Clin Pharmacol : GRADES Parameter Origin ALT (ULNR) AST (ULNR) Bilirubin (ULNR) Alk Phosphatasis (ULNR) CPI 1.3 (or # 70 IU/L) to 3 ULNR 3 to 5 * 5 to 10 FDA 1.1 to 2.5 ULNR 2.6 to 5 5 to 10 NIH 1.25 to 2.5 ULNR 2.5 to 5 5 to 10 CPI 1.2 (or # 70 IU/L) to 3 ULNR 3 to 5 * 5 to 10 FDA 1.1 to 2.5 ULNR 2.6 to 5 5 to (or # 35 IU/L) if change from 2 to 2.5 * 2.5 to 3 CPI baseline > 10 mmol/l to 2 ULNR FDA, if LFT normal 1.1 to 1.5 ULNR 1.6 to 2 2 to 3 FDA, if increase of LFT 1.1 to to to 1.75 NIH 1.25 to 2.5 ULNR 2.5 to 5 * 5 to 10 CPI 1.1 (or # 132 IU/L) to 2 ULNR 2.1 to to 10 FDA 1.1 to 2 ULNR 2.1 to to 10 NIH 1.25 to 2.5 ULNR 2.6 to 5 5 to 10 HY'S Law ALT > 3 ULNR and Bilirubin > 2 ULNR induces upgrading to level 3 The appearance of worsening of fatigue, nausea, vomiting, fever, rash eosinophilia or right upper quadrant pain or tenderness or the association to INR superior to 1.5 induces an upgrading. 35 ULNR: Upper limit of normal range / LLNR: Lower limit of normal range / CPI: Club phase I task force

36 PLATELETS PARAMETER Grades Parameter Origin Platelets decrease (giga/l) assuming no platelet cluster CPI 130 to 120 giga 120 to 100 giga < 100 giga AP 36

37 PLATELETS PARAMETER Grades Parameter Origin Platelets decrease (giga/l) assuming no platelet cluster CPI 130 to 120 giga 120 to 100 giga < 100 giga FDA 140 to 125 giga 124 to 100 giga 99 to 25 giga Very similar AP 37

38 PLATELETS PARAMETER Grades Parameter Origin Platelets decrease (giga/l) assuming no platelet cluster CPI 130 to 120 giga 120 to 100 giga FDA 140 to 125 giga 124 to 100 giga < 100 giga 99 to 25 giga NIH 125 to 100 giga 99 to to 25 Too low values in NIH guideline due to AIDS treatment specificities AP 38

39 The same process could be applied on ECG/Vital signs or on any finding 30 MS 39

40 THIRD PART Decision making process: the «stopping rules» CPI proposals 40

41 DECISION MAKING PROCESS STOPPING RULES Difficulty due to usual conflict-of-interest : Subject safety (and protection) caution Learning on drug pushing dose escalation Therefore stopping rules are required 41

42 Stopping rules CPI proposal 42

43 DECISION PROCESS : STOPPING RULE Three criteria will lead the process : Adverse Events Grades (severity) Number of subjects experiencing similar Adverse Events Drug relationship : Active or Placebo Stopping rule at the Individual level: if any event of grade equal or greater than 3 Stopping rules at a Cohort level : if any event of grade equal or greater than 3 Grade 2 should be considered at least as a safety alert 43

44 DECISION TREE : STOPPING RULES + 44

45 DECISION TREE : STOPPING RULES + 45

46 DECISION TREE : STOPPING RULES + 46

47 DECISION TREE : STOPPING RULES + 47

48 DECISION TREE : STOPPING RULES + 48

49 DECISION TREE : STOPPING RULES + 49

50 DECISION TREE : STOPPING RULES MSMS 50 50

51 CONCLUSION 1. Points to consider, but not guideline 2. Improved proposals, due to accurate bases & methods 3. Fit to healthy subject and all types of FIMs 4. Adjust if PD objective (ie. aptt anticoagulant) ; those thresholds are not dedicated as limit for screening 5. Suggestions but decision upon investigator responsibility 51

52 EXAMPLES OF STOPPING RULES SAE not appropriate Number of subjects to be considered depends on the type and severity of the AEs Moderate or severe AEs in 50% or more of the cohort Severe AEs of the same kind in more than 2 subjects (out of 8) ALT greater than 3 ULNR in 50% or more of the cohort Hy s law in more than 2 or 3 subjects (out of 8) QTcF greater than 500msec in 50% or more of the cohort 52

53 EXAMPLES OF STOPPING RULES Drug related severe adverse events (AE s) of the same character in 2 or more subjects. Clinically significant laboratory abnormalities of the same character in 3 or more subjects (ALAT > 3 ULN). Clinically significant changes in vital signs of the same character in 3 or more subjects: blood pressure consistently greater than 160 mmhg associated with an increase from baseline greater than 20 mmhg. Clinically significant changes in ECGs of the same character in 3 or more subjects: QTc greater than 500 ms with an increase from baseline greater than 60 ms. 53

54 The working party thank you for your attention! 54

55 Intensity Grade 1 (Mild) Grade 2 (Moderate) Grade 3 (Severe) General definition Possible modulations based on: Asthenia/ Drowsiness Does not interfere with activity number of episodes and/or Does not interfere with usual and social activity Interferes with activity, no treatment except acetaminophen Prevents daily activity or requires treatment Grade 4 (Potentially lifethreatening) Emergency room visit or hospitalization duration of symptoms and/or associated malaise or general effects. Interfere with usual and social activity, no treatment Headache Transient Interferes with activity, no treatment except acetaminophen Pain (irrespective of location) STOPPING RULES : ADVERSE EVENT EXAMPLES French Club Phase I Working group : Br J Clin Pharmacol : Transient Several hours but less <12 hours. Interferes with activity, no treatment except acetaminophen Several hours but less <12 hours. Prevents daily activity or requires treatment Prevents daily activity or requires treatment > 12 h, presence during the night. Prevents daily activity or requires treatment > 12 h, presence during the night Emergency room visit or hospitalization Emergency room visit or hospitalization Emergency room visit or hospitalization Malaise/syncope Does not interfere Interferes with activity, no Syncope, or prevents Repeated syncopes. with activity treatment daily activity, Emergency room visit 55 or Joint conference AGAH - BAPU - Club Phase I - AHPPI - Berlin or requires - 31 March treatment to 1st April hospitalization 2011